Pharmacokinetics of Diclofenac and Hydroxypropyl-ß-Cyclodextrin (HPßCD) Following Administration of Injectable HPßCD-Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment.

Given their established analgesic properties, nonsteroidal anti-inflammatory drugs (NSAIDs) represent an important postoperative pain management option. This study investigated: (1) the effects of mild or moderate renal insufficiency and mild hepatic impairment on the pharmacokinetics (PK) of diclofenac and hydroxypropyl-ß-cyclodextrin (HPßCD) following administration of the injectable NSAID HPßCD-diclofenac; and (2) the PK of HPßCD following administration of HPßCD-diclofenac and intravenous itraconazole formulated with HPßCD in healthy adults. Diclofenac clearance (CL) and volume of distribution (Vz ) tended to increase with decreasing renal function (moderate insufficiency versus mild insufficiency or healthy controls). Regression analysis demonstrated a significant relationship between Vz (but not CL or elimination half-life, t½ ) and renal function. HPßCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t½ . There were no significant differences in diclofenac or HPßCD PK in subjects with mild hepatic impairment versus healthy subjects. Exposure to HPßCD in healthy subjects following HPßCD-diclofenac administration was ∼12% of that with intravenous itraconazole, after adjusting for dosing schedule and predicted accumulation (<5% without adjustment). With respect to PK properties, these results suggest that HPßCD-diclofenac might be administered to patients with mild or moderate renal insufficiency or mild hepatic impairment without dose adjustment (NCT00805090).

A Phase I study evaluating the effect of age and weight on the pharmacokinetics of an injectable formulation of diclofenac solubilized with hydroxypropyl-ß-cyclodextrin.

PURPOSE: The analgesic and opioid-sparing effects of nonsteroidal anti-inflammatory drugs can be beneficial in postoperative populations. Hydroxypropyl-ß-cyclodextrin (HPßCD)-diclofenac is an injectable formulation of diclofenac solubilized with HPßCD that is administered as a low-volume intravenous bolus. This open-label, single-dose study examined the effects of age and weight on the pharmacokinetic (PK) profile of HPßCD-diclofenac. METHODS: Eighty-eight adult volunteers were enrolled. An age-based cohort included 34 subjects 55-82 years old stratified into three groups and receiving HPßCD-diclofenac 18.75 mg. A weight-based cohort included 54 subjects stratified into five groups based on body weight and body mass index and receiving HPßCD-diclofenac 37.5 mg. PK analysis was performed on blood samples collected predosing and at predefined intervals (5, 10, 20, 30, and 45 minutes; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 18 hours) postdosing. Diclofenac PK parameters were examined in the individual cohorts, and regression analyses of the relationship between age, weight, and PK parameters were performed on pooled data from all enrolled subjects. RESULTS: Examination of the age-based cohort revealed similar diclofenac PK parameters across age groups. PK parameters were likewise similar across weight groups in the weight-based cohort. Regression analysis on pooled data from the age- and weight-based cohorts revealed that increasing body weight was associated with a significant increase in diclofenac clearance (CL), suggesting decreased exposure in high-weight patients. Analysis of the pooled population also demonstrated an inverse relationship between age and elimination half-life (t1/2), likely due to a decrease in the volume of distribution (Vz) with increased age, not a change in CL. There were no deaths, serious adverse events, or adverse events that led to discontinuation. CONCLUSION: This study suggests that the CL of diclofenac is not dependent on age in elderly subjects receiving HPßCD-diclofenac but indicates that diclofenac CL increases with increasing body weight.

Pharmacokinetic and Pharmacodynamic Equivalence of Epoetin Hospira and Epogen After Single Subcutaneous Doses to Healthy Male Subjects.

PURPOSE: The purpose of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of single 100 U/kg subcutaneous doses of Epoetin Hospira and Epogen in healthy male subjects as part of an overall program to demonstrate biosimilarity of Epoetin Hospira to the reference product Epogen. METHODS: This single-center, open-label, randomized, 2-period, crossover study was conducted in 81 healthy male subjects. Subjects were randomized to Sequence 1, in which they received 100 U/kg of Epoetin Hospira or to sequence 2, in which they received 100 U/kg Epogen subcutaneously in the first study period and the alternative treatment in the second study period. Blood was collected for determination of baseline-adjusted epoetin concentrations (BAECs) for pharmacokinetics and for determination of reticulocyte percentage of total erythrocytes for pharmacodynamics throughout both study periods. The primary PK end points were the geometric mean ratios (GMRs) of the 2 treatments for AUC0-t and Cmax based on the BAEC, and the primary PD end points were the GMRs of the 2 treatments for AUC0-t and Cmax for reticulocyte percentage. FINDINGS: The GMRs of Epoetin Hospira to Epogen for the BAEC-derived PK parameters were 1.05 for AUC0-t with a 90% CI of 1.01 to 1.11, and 1.09 for Cmax with a 90% CI of 1.01 to 1.18, with both 90% CIs contained within the prespecified equivalence margin of 0.80 to 1.25. The GMRs (Epoetin Hospira/Epogen) for the reticulocyte percentage-derived PD parameters were 1.01 for AUC0-t with a 95% CI of 0.98 to 1.05, and 1.02 for Cmax with a 95% CI of 0.98 to 1.06, with both 95% CIs contained within the prespecified equivalence margin of 0.80 to 1.25. Overall, the adverse events were of similar frequency (11.7% and 13.9% for Epoetin Hospira and Epogen, respectively) and severity between treatments. One subject had a positive anti- recombinant human erythropoietin antibody result by radioimmunoprecipitation assay before dosing and throughout the conduct of the study with negative neutralizing antibodies and with no evidence of clinical deterioration or impact on the pharmacokinetics, pharmacodynamics, or safety. IMPLICATIONS: The results of this study established the PK and PD equivalence of single 100 U/kg subcutaneous doses of the proposed biosimilar Epoetin Hospira to the reference product Epogen in healthy male subjects and support the overall demonstration of biosimilarity of Epoetin Hospira and Epogen.

Pharmacodynamic and Pharmacokinetic Equivalences of Epoetin Hospira and Epogen(®) After Multiple Subcutaneous Doses to Healthy Male Subjects.

PURPOSE: The purpose of this study was to evaluate the pharmacodynamic (PD) and pharmacokinetic (PK) equivalences of multiple doses of the proposed biosimilar Epoetin Hospira to the reference product Epogen(⁎), when each is administered three times per week over 28 days to healthy male subjects METHODS: This single center, open-label, randomized, parallel group study was conducted in 129 healthy male subjects. Subjects were randomized to receive 100 U/kg Epoetin Hospira or 100 U/kg Epogen, each administered subcutaneously 3 times per week over 28 days. Blood was collected for determination of hemoglobin (Hb) concentrations for PD properties and for determination of epoetin concentrations for PK properties. The primary PD end point was the geometric mean ratio (GMR) of the 2 treatments for area under the effect curve for Hb from day 1 through 48 hours after the final dose of study drug administration on day 26, and the primary PK end point was the GMR of the 2 treatments for AUC0-48 and Cmax for epoetin after the final dose of study drug on day 26. FINDINGS: The GMR (Epoetin Hospira/Epogen) for the area under the effect curve for Hb from day 1 through 48 hours after the final dose of study drug administration on day 26 was 1.006 with a 95% CI of 0.996 to 1.016, which was contained within the prespecified equivalence margin of 0.965 to 1.035. The GMRs (Epoetin Hospira/Epogen) for the epoetin-derived PK parameters were 0.974 for AUC0-48 with a 90% CI of 0.896 to 1.059, and 0.938 for Cmax with a 90% CI of 0.839 to 1.049, with both 90% CIs contained within the prespecified equivalence margin of 0.80 to 1.25. The incidence (21.2% and 23.8% for Epoetin Hospira and Epogen, respectively) and severity of adverse events were similar between the 2 groups. One subject in each treatment group had a positive recombinant human erythropoietin antibody result by radioimmunoprecipitation assay before dosing and throughout study conduct with negative immunoglobulin M and neutralizing antibodies and with no evidence of clinical deterioration or of impact on PD, PK, or safety profile. IMPLICATIONS: The results of this study established PD and PK equivalences of multiple subcutaneous doses of the proposed biosimilar Epoetin Hospira to the reference product Epogen in healthy male subjects, and supported the overall demonstration of biosimilarity of Epoetin Hospira and Epogen.

Pharmacokinetic characterization of mangosteen (Garcinia mangostana) fruit extract standardized to α-mangostin in C57BL/6 mice.

Previously, we have reported the pharmacokinetic (PK) properties of α-mangostin in mice. For this study, we evaluated the PK profile of α-mangostin using a standardized mangosteen extract in C57BL/6 mice. The primary objective was to determine the PK properties of α-mangostin when administered as an extract. This experiment was designed to test our primary hypothesis that α-mangostin in an extract should achieve a desirable PK profile. This is especially relevant as dietary supplements of mangosteen fruit are regularly standardized to α-mangostin. Mice received 100 mg/kg of mangosteen fruit extract orally, equivalent to 36 mg/kg of α-mangostin, and plasma samples were analyzed over a 24-hour period. Concentrations of α-mangostin were determined by liquid chromatography-tandem mass spectrometry. In addition, we evaluated the stability in the presence of phase I and phase II enzymes in liver and gastrointestinal microsomes. Furthermore, we identified evidence of phase II metabolism of α-mangostin. Further research will be required to determine if less abundant xanthones present in the mangosteen may modulate the PK parameters of α-mangostin.

Single-dose and multiple-dose pharmacokinetics and dose proportionality of intravenous and intramuscular HPßCD-diclofenac (Dyloject) compared with other diclofenac formulations.

STUDY OBJECTIVE: To evaluate single- and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-ß-cyclodextrin (HPßCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration. DESIGN: Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study. SETTING: Clinical research center. SUBJECTS: Healthy adult volunteers. INTERVENTION: Study 1: Subjects received HPßCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPßCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods. MEASUREMENTS AND MAIN RESULTS: Study 1: IV HPßCD-diclofenac had a higher peak plasma concentration (Cmax ) and earlier time to reach maximum plasma concentration (Tmax ), but equivalent plasma exposure (area under the curve from time zero to t [AUC0-t ]) to IV Voltarol. The geometric mean ratio of HPßCD-diclofenac (IV) to Voltarol (IV) for AUC0-t was 106.27%. The geometric mean ratio of HPßCD-diclofenac (IM) to Voltarol (IM) for AUC0-t was 110.91%. The geometric mean ratio of HPßCD-diclofenac (IV) to HPßCD-diclofenac (IM) for AUC0-t was 101.25%. The geometric mean ratio of HPßCD-diclofenac (IM) to Voltarol (IV) for AUC0-t was 104.96%. Study 2: Cmax for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPßCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ng·hour/ml) and 37.5 mg (1843 ng·hour/ml) IV HPßCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ng·hour/ml). CONCLUSIONS: Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPßCD-diclofenac compared with Voltarol and after IM administration of HPßCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPßCD-diclofenac was equivalent to IV administration of HPßCD-diclofenac and IV administration of Voltarol. Study 2: HPßCD-diclofenac showed dose proportionality after single- and multiple-dose administration and no accumulation of HPßCD-diclofenac. HPßCD-diclofenac was safe and well tolerated following IV and IM administration.

Single dose oral pharmacokinetic profile of α-mangostin in mice.

The mangosteen fruit (Garcinia mangostana) is a rich source of dietary xanthones with the most prominent being α-mangostin. Dietary xanthones have been reported to have a variety of health promoting properties. Until now, in vivo studies on the pharmacokinetic profile of α-mangostin are limited. For this study we employed an LC/MS/MS assay to determine the pharmacokinetic properties of α-mangostin suspension in cottonseed oil in C57BL/6 Mice. Mice were administered 100 mg/kg of α-mangostin by oral gavage and the plasma levels were analyzed over a 24 hour period. We observed the degree of exposure (i.e. area under the curve) of α-mangostin to be 5,736 nmol/L/hr and the maximum plasma concentration was 1,382 nmol/L. Furthermore, we provide evidence that α-mangostin undergoes glucuronidation into monoglucuronide and diglucuronide metabolites. Our study demonstrated that α-mangostin when administered in cotton seed oil to mice at a dose equivalent to 615 mg in a 90kg human adult achieves an approximate maximum plasma concentration of 1,300 nmol/L and is detectable for up to 24 hours. Further research is needed to understand the relationship between the pharmacokinetic properties of α-mangostin following oral administration and reported health benefits.

Preclinical disposition of GDC-0973 and prospective and retrospective analysis of human dose and efficacy predictions.

[3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-((S)-3-hydroxy-3-piperidin-2-yl-azetidin-1-yl)-methanone (GDC-0973) is a potent and highly selective inhibitor of mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase (ERK) 1/2 (MEK1/2), a MAPK kinase that activates ERK1/2. The objectives of these studies were to characterize the disposition of GDC-0973 in preclinical species and to determine the relationship of GDC-0973 plasma concentrations to efficacy in Colo205 mouse xenograft models. The clearance (CL) of GDC-0973 was moderate in mouse (33.5 ml · min(-1) · kg(-1)), rat (37.9 ± 7.2 ml · min(-1) · kg(-1)), and monkey (29.6 ± 8.5 ml · min(-1) · kg(-1)). CL in dog was low (5.5 ± 0.3 ml · min(-1) · kg(-1)). The volume of distribution across species was large, 6-fold to 15-fold body water; half-lives ranged from 4 to 13 h. Protein binding in mouse, rat, dog, monkey, and human was high, with percentage unbound, 1 to 6%. GDC-0973-related radioactivity was rapidly and extensively distributed to tissues; however, low concentrations were observed in the brain. In rats and dogs, [(14)C]GDC-0973 was well absorbed (fraction absorbed, 70-80%). The majority of [(14)C]GDC-0973-related radioactivity was recovered in the bile of rat (74-81%) and dog (65%). The CL and volume of distribution of GDC-0973 in human, predicted by allometry, was 2.9 ml · min(-1) · kg(-1) and 9.9 l/kg, respectively. The predicted half-life was 39 h. To characterize the relationship between plasma concentration of GDC-0973 and tumor growth inhibition, pharmacokinetic-pharmacodynamic modeling was applied using an indirect response model. The KC(50) value for tumor growth inhibition in Colo205 xenografts was estimated to be 0.389 µM, and the predicted clinical efficacious dose was ∼10 mg. Taken together, these data are useful in assessing the disposition of GDC-0973, and where available, comparisons with human data were made.